We have previously established that rat and human hepatic HMG-CoA reductase activity is modulated in vitro and in vivo in a bicyclic cascade system involving reversible phosphorylation of both HMG-CoA reductase and reductase Kinase. Recently we have demonstrated the regulation of HMG-CoA reductase and cell cycle progression by thyrotropin (TSH) in FRTL-5 rat thyroid cells. When these cells were made quiescent, and synchronized by TSH starvation, in the presence of 0.2% serum, this hormone increased rate of cholesterol synthesis by 8 fold. Time course of TSH effect on cholesterol synthesis suggests that this process is necessary for quiescent FRTL-5 cells to enter the cell cycle. Thymidine incorporation into DNA, measured under identical conditions of TSH starvation/challenge was also increased. The increase in cholesterol synthesis was due to increase in reductase messenger RNA (up to 8-fold) caused by proportional increase in the rate of gene transcription. The effect of TSH on cholesterol synthesis and reductase gene expression is likely to be mediated by cAMP, which mimicked the effect of the hormone. The data suggested that an active cholesterol biosynthetic pathway is required for DNA synthesis to occur. In order to understand coordinate regulation of HMG-CoA reductase, cholesterol synthesis and the role of LDL (apoB-100) in the transport and homeostasis of cellular cholesterol, role of apoB-100 in plasma lipid and lipoprotein transport and metabolism has been studied. We have demonstrated in vitro that phosphorylation of human apoB-100 by protein kinase is associated with an incorporation of 4 mol/mol of apoB-100. In HepG-2 cells, both cellular and secreted apoB-100 is phosphorylated. Incubation of HepG-2 cells with phorbol ester caused a concomitant increase in protein kinase C activity, increased in cellular phosphorylation of apoB-100 coupled with enhanced degradation of phosphorylated apoB-100 in comparison to controls.